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ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

Balliol College, University of Oxford, Oxford OX1 3BJ, UK
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
Nuffield Division of Clinical Laboratory Science, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
Authors to whom correspondence should be addressed.
Metabolites 2019, 9(12), 287;
Received: 25 October 2019 / Revised: 19 November 2019 / Accepted: 21 November 2019 / Published: 25 November 2019
(This article belongs to the Special Issue Metabolomics in the Study of Disease)
Adhesion G Protein-Coupled Receptor L4 (ADGRL4/ELTD1) is an endothelial cell adhesion G protein-coupled receptor (aGPCR) which regulates physiological and tumour angiogenesis, providing an attractive target for anti-cancer therapeutics. To date, ADGRL4/ELTD1′s full role and mechanism of function within endothelial biology remains unknown, as do its ligand(s). In this study, ADGRL4/ELTD1 silencing, using two independent small interfering RNAs (siRNAs), was performed in human umbilical vein endothelial cells (HUVECS) followed by transcriptional profiling, target gene validation, and metabolomics using liquid chromatography-mass spectrometry in order to better characterise ADGRL4/ELTD1′s role in endothelial cell biology. We show that ADGRL4/ELTD1 silencing induced expression of the cytoplasmic metabolic regulator ATP Citrate Lyase (ACLY) and the mitochondria-to-cytoplasm citrate transporter Solute Carrier Family 25 Member 1 (SLC25A1) but had no apparent effect on pathways downstream of ACLY (fatty acid and cholesterol synthesis or acetylation). Silencing induced KIT expression and affected the Notch signalling pathway, upregulating Delta Like Canonical Notch Ligand 4 (DLL4) and suppressing Jagged Canonical Notch Ligand 1 (JAG1) and Hes Family BHLH Transcription Factor 2 (HES2). The effect of ADGRL4/ELTD1 silencing on the cellular metabolic profile was modest but several metabolites were significantly affected. Cis-aconitic acid, uridine diphosphate (UDP)-glucoronate, fructose 2,6-diphosphate, uridine 5-diphosphate, and aspartic acid were all elevated as a result of silencing and phosphocreatine, N-acetylglutamic acid, taurine, deoxyadenosine triphosphate, and cytidine monophosphate were depleted. Metabolic pathway analysis implicated ADGRL4/ELTD1 in pyrimidine, amino acid, and sugar metabolism. In summary, this study shows that ADGRL4/ELTD1 impacts core components of endothelial metabolism and regulates genes involved in endothelial differentiation/homeostasis and Notch signalling. View Full-Text
Keywords: ADGRL4/ELTD1; metabolomics; adhesion GPCR ADGRL4/ELTD1; metabolomics; adhesion GPCR
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MDPI and ACS Style

Favara, D.M.; Zois, C.E.; Haider, S.; Pires, E.; Sheldon, H.; McCullagh, J.; Banham, A.H.; Harris, A.L. ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile. Metabolites 2019, 9, 287.

AMA Style

Favara DM, Zois CE, Haider S, Pires E, Sheldon H, McCullagh J, Banham AH, Harris AL. ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile. Metabolites. 2019; 9(12):287.

Chicago/Turabian Style

Favara, David M., Christos E. Zois, Syed Haider, Elisabete Pires, Helen Sheldon, James McCullagh, Alison H. Banham, and Adrian L. Harris 2019. "ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile" Metabolites 9, no. 12: 287.

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